Summary Staphylococcus aureus is a major human pathogen of the respiratory tract and influenza co- infection is a major predisposing factor for subsequent infection. Increasing antibiotic resistance is a major concern and in the absence of a protective vaccine understanding the bacterial and host processes in infection will identify new treatment targets. The host inflammatory processes involved in S. aureus infection of the lung are not well understood, but we have identified the type III interferon pathway to be activated upon S. aureus infection. Type III interferon signaling contributes to the ability of S. aureus to colonize the nasopharynx as well as in the lung during acute pneumonia where they contribute to excessive immunopathology. The parents grant aims to delineate the multiple mechanisms behind type III interferons contributing to S. aureus- induced disease. Aim 1 examines the capacity of type III IFNs to inhibit neutrophil function and their signaling. In Aim 2 the capacity of type III IFN to influence the inflammasome is examined. In Aim 3 how conserved the activation of this pathway is across a variety of clinical specimens will be determined and the major cell types involved in producing type III IFN will be examined. In this minority supplement application we address the involvement of the epithelium in directing the type III interferon response. Using in vitro systems and in vivo models of infection we will determine how the epithelium contributes to: inflammatory cytokine production, killing of S. aureus and its influence over professional phagocyte function. At the conclusion of these studies, we will have expanded our knowledge on how type III IFNs contribute to the pathogenesis of S. aureus pneumonia, and will have identified targetable mechanisms for therapeutic amelioration of host immunopathology due to IFN production.